During metabolic alkalosis, the type B intercalated cell actively secretes HCO3- and absorbs Cl- across the apical plasma membrane, through the CI-/HCO3- exchanger, pendrin. The result is attenuation of the alkalemia. Pendrin-mediated Cl- absorption is also an important mechanism for the vascular volume expansion and hypertension observed in rodent models of NaCI-sensitive hypertension, such as following the administration of a high NaCI diet and aldosterone analogues. Thus Cl- transport processes, such as pendrin, are critcal in the generation of salt-sensitive hypertension. Our laboratory has evidence that angiotensin II directly regulates pendrin-mediated Cl- uptake, independent of aldosterone. Moreover, in the CCD, the angiotensin ll-mediated increase in NaCI absorption likely requires the coordinated action of both pendrin and the epithelial Na+ channel, ENaC. The molecular mechanism for the regulation of pendrin by angiotensin II and how ENaC and pendrin interact to mediate NaCI absorption is the subject of the present proposal. The aims of this proposal are 1) To determine the mechanism whereby angiotensin II stimulates pendrin-mediated CI-/HCO3- exchange in vitro and to determine how pendrin and ENaC interact following angiotensin II to increse NaCI absorption. 2) To determine the mechanism of the long-term regulation of pendrin by angiotensin. 3) To determine the mechanism of the interdependency of pendrin and ENaC expression. To accomplish these objectives Slc26a4 (+/+) and Slc26a4 (-/-) mice will be studied using quantitative real time PCR, light microscopic immunonistochemistry, immunogold cytochemistry, immunoblots and transport studies in vitro in perfused renal tubules . Whole animal studies will be further employed in balance studies and measurements of blood pressure and GFR. Lay summary: Our laboratory has observed that pendrin, a protein that promotes absorption of chloride in the kidney, is important in the generation of high blood pressure. In addition, activity of pendrin is very dependent on activity of a specific kidney sodium transporter, called ENaC. This proposal will explore how pendrin controls absorption of Cl- by the kidney and why activity of pendrin and ENaC are so dependent on each other.